Our study is designed to assess if exosomes released from chronic myelogenous leukemia (CML) cells may modulate angiogenesis. We have isolated and characterized the exosomes generated from LAMA84 CML ...cells and demonstrated that addition of exosomes to human vascular endothelial cells (HUVEC) induces an increase of both ICAM‐1 and VCAM‐1 cell adhesion molecules and interleukin‐8 expression. The stimulation of cell‐cell adhesion molecules was paralleled by a dose‐dependent increase of adhesion of CML cells to a HUVEC monolayer. We further showed that the treatment with exosomes from CML cells caused an increase in endothelial cell motility accompanied by a loss of VE‐cadherin and β‐catenin from the endothelial cell surface. Functional characterization of exosomes isolated from CML patients confirmed the data obtained with exosomes derived from CML cell line. CML exosomes caused reorganization into tubes of HUVEC cells cultured on Matrigel. When added to Matrigel plugs in vivo, exosomes induced ingrowth of murine endothelial cells and vascularization of the Matrigel plugs. Our results suggest for the first time that exosomes released from CML cells directly affect endothelial cells modulating the process of neovascularization.
Los valores que promueven la salud física, la exaltación de la belleza y la conservación del cuerpo en su fuerza juvenil están cristalizándose cada vez más en la sociedad moderna. El cuidado del ...cuerpo, considerado como una carcasa necesaria para asegurar la supervivencia de nuestra identidad, se ha convertido en una búsqueda obsesiva que compromete la mayor parte de nuestra existencia. La intención de este trabajo es poner de relieve cómo el culto a la juventud, al cuerpo perfecto y a la educación sobre una nutrición adecuada, junto con el notable progreso de las ciencias biotecnológicas, se han convertido en hábitos diarios que requieren la mayor parte de nuestro tiempo libre y contribuyen a la alteración de la imagen del cuerpo considerado como el punto de apoyo de la existencia de la identidad.Palabras clave: cuerpo, sport, juventud, tecnologías, inmortalidad, identidad.Abstract:The values of promotion of physical well-being, of the exaltation of beauty and of the preservation of the body in its juvenile strength are increasingly crystallizing I n this modern society. The attention towards the care of the body, considered as a necessary shell to insure the survival of our identity, has become a truly obsessive search that engages much of our existence. The intention of this essay is to highlight how the cult of youth, of the perfect physical shape and of the appropriate nutritional education, together with the impressive progresses of biotechnological sciences, has become habits requiring much of our free time and contributing to the alteration of the image of the body, that is considered as the fulcrum of the identity-making existence.Keywords: body, sport, youth, technologies, immortality, identity.
Refractory acute myeloid leukaemia is very difficult to treat and represents an unmet clinical need. In recent years, new drugs and combinations of drugs have been tested in this category, with ...encouraging results. However, all treated patients relapsed and died from the disease. The only curative option is allogeneic transplantation through a graft from a healthy donor immune system. Using myeloablative conditioning regimens, the median overall survival regimens is 19%. Several so-called sequential induction chemotherapies followed by allogeneic transplantation conditioned by reduced intensity regimens have been developed, improving the overall survival to 25-57%. In the allogeneic transplantation field, continuous improvements in practices, particularly regarding graft versus host disease prevention, infection prevention, and treatment, have allowed us to observe improvements in survival rates. This is true mainly for patients in complete remission before transplantation and less so for refractory patients. However, full myeloablative regimens are toxic and carry a high risk of treatment-related mortality. In this review, we describe the results obtained with the different modalities used in more recent retrospective and prospective studies. Based on these findings, we speculate how allogeneic stem cell transplantation could be modified to maximise its therapeutic effect on refractory acute myeloid leukaemia.
Natural killer (NK) cells from patients with familial hemophagocytic lymphohistiocytosis because of PRF1 (FHL2, n = 5) or MUNC13-4 (FHL3, n = 8) mutations were cultured in IL-2 prior to their use in ...various functional assays. Here, we report on the surface CD107a expression as a novel rapid tool for identification of patients with Munc13-4 defect. On target interaction and degranulation, FHL3 NK cells displayed low levels of surface CD107a staining, in contrast to healthy control subjects or perforin-deficient NK cells. B-EBV cell lines and dendritic cell targets reveal the FHL3 NK-cell defect, whereas highly susceptible tumor targets were partially lysed by FHL3 NK cells expressing only trace amounts of Munc13-4 protein. Perforin-deficient NK cells were completely devoid of any ability to lyse target cells. Cytokine production induced by mAb-crosslinking of triggering receptors was comparable in patients and healthy control subjects. However, when cytokine production was induced by coculture with 721.221 B-EBV cells, FHL NK cells resulted in high producers, whereas control cells were almost ineffective. This could reflect survival versus elimination of B-EBV cells (ie, the source of NK-cell stimulation) in patients versus healthy control subjects, thus mimicking the pathophysiologic scenario of FHL.
IL-17A is a T cell-specific cytokine that is involved in chronic inflammations, such as Mycobacterium infection, Crohn's disease, rheumatoid arthritis and multiple sclerosis. Mouse models have ...explained the molecular basis of IL-17A production and have shown that IL-17A has a positive effect not only on granuloma formation and neurodegeneration through unknown mechanisms, but also on bone resorption through Receptor activator of NF-kappaB ligand (RANKL) induction in osteoblasts. Langerhans cell histiocytosis (LCH) is a rare disease of unknown etiology, lacking an animal model, that cumulates symptoms that are found separately in various IL-17A-related diseases, such as aggressive chronic granuloma formation, bone resorption and soft tissue lesions with occasional neurodegeneration. We examined IL-17A in the context of LCH and found that there were high serum levels of IL-17A during active LCH and unexpected IL-17A synthesis by dendritic cells (DCs), the major cell type in LCH lesions. We also found an IL-17A-dependent pathway for DC fusion, which was highly potentiated by IFN-gamma and led to giant cells expressing three major tissue-destructive enzymes: tartrate resistant acidic phosphatase and matrix metalloproteinases 9 and 12. IFN-gamma expression has been previously documented in LCH and observed in IL-17A-related diseases. Notably, serum IL-17A-dependent fusion activity correlates with LCH activity. Thus, IL-17A and IL-17A-stimulated DCs represent targets that may have clinical value in the treatment of LCH and other IL-17A-related inflammatory disorders.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase family member. Mutations in
, as well known, represent the most common genomic alteration in acute myeloid leukemia (AML), identified ...in approximately one-third of newly diagnosed adult patients. In recent years, this has represented an important therapeutic target. Drugs such as midostaurin, gilteritinib, and sorafenib, either alone in association with conventional chemotherapy, play a pivotal role in AML therapy with the mutated
gene. A current challenge lies in treating forms of AML with extramedullary localization. Here, we describe the general features of myeloid sarcoma and the ability of a targeted drug, i.e., gilteritinib, approved for relapsed or refractory disease, to induce remission of these extramedullary leukemic localizations in AML patients with
mutation, analyzing how in the literature, there is an important development of cases describing this promising potential for care.
Variant Philadelphia (Ph) chromosome translocations have been reported in 5%-10% of patients with newly diagnosed chronic myeloid leukemia (CML). Variant translocations may involve one or more ...chromosomes in addition to 9 and 22, and can be generated by 2 different mechanisms, 1-step and 2-step rearrangements, as revealed by fluorescence in situ hybridization. The prognostic significance of the occurrence of variant translocations has been discussed in previous studies. The European LeukemiaNet recommendations do not provide a “warning” for patients with variant translocations, but there is limited information about their outcome after therapy with tyrosine kinase inhibitors. To identify the role of variant translocations in early chronic phase (CP) CML patients treated with imatinib mesylate, we performed an analysis in a large series of 559 patients enrolled in 3 prospective imatinib trials of the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) Working Party on CML. Variant translocations occurred in 30 patients (5%). Our data show that the presence of variant translocations has no impact on the cytogenetic and molecular response or on outcome, regardless of the involvement of different mechanisms, the number of involved chromosomes, or the presence of deletions. Therefore, we suggest that patients with variant translocations do not constitute a “warning” category in the imatinib era. This study is registered at www.clinicaltrials.gov as NCT00514488 and NCT00510926.
Chimeric antigen receptor T (CAR-T) cells are a treatment option for patients with relapse/refractory (R/R) non-Hodgkin lymphoma (NHL), acute lymphoid leukemia and multiple myeloma. To date, diffuse ...large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL) have been successfully treated with CAR-T cells directed against the CD19 antigen. However, when R/R disease persists after several treatment lines, patients with these diseases are often referred to transplantation centres to receive allogeneic stem cell transplantation (ALLO-SCT). ALLO-SCT and CAR-T cells share mechanism of actions, inducing immune effects of
-cells (and other cells after transplantation) against lymphoma cells, but they differ in several other characteristics. These differences justify unique positioning of each therapy within treatment algorithms. In this paper, we analyzed the results obtained after ALLO-SCT and CAR-T-cell therapy in patients with aggressive lymphomas (large B-cell lymphoma and MCL) to identify the ideal scenarios in which these 2 immunological therapies should be employed.
PDF
